Author:
Lazniewska Joanna,Li Ka Lok,Johnson Ian R. D.,Sorvina Alexandra,Logan Jessica M.,Martini Carmela,Moore Courtney,Ung Ben S.-Y.,Karageorgos Litsa,Hickey Shane M.,Prabhakaran Sarita,Heatlie Jessica K.,Brooks Robert D.,Huzzell Chelsea,Warnock Nicholas I.,Ward Mark P.,Mohammed Bashir,Tewari Prerna,Martin Cara,O’Toole Sharon,Edgerton Laura Bogue,Bates Mark,Moretti Paul,Pitson Stuart M.,Selemidis Stavros,Butler Lisa M.,O’Leary John J.,Brooks Douglas A.
Abstract
AbstractProstate cancer (PCa) development and progression relies on the programming of glucose and lipid metabolism, and this involves alterations in androgen receptor expression and signalling. Defining the molecular mechanism that underpins this metabolic programming will have direct significance for patients with PCa who have a poor prognosis. Here we show that there is a dynamic balance between sortilin and syndecan-1, that reports on different metabolic phenotypes. Using tissue microarrays, we demonstrated by immunohistochemistry that sortilin was highly expressed in low-grade cancer, while syndecan-1 was upregulated in high-grade disease. Mechanistic studies in prostate cell lines revealed that in androgen-sensitive LNCaP cells, sortilin enhanced glucose metabolism by regulating GLUT1 and GLUT4, while binding progranulin and lipoprotein lipase (LPL) to limit lipid metabolism. In contrast, in androgen-insensitive PC3 cells, syndecan-1 was upregulated, interacted with LPL and colocalised with β3 integrin to promote lipid metabolism. In addition, androgen-deprived LNCaP cells had decreased expression of sortilin and reduced glucose-metabolism, but increased syndecan-1 expression, facilitating interactions with LPL and possibly β3 integrin. We report a hitherto unappreciated molecular mechanism for PCa, which may have significance for disease progression and how androgen-deprivation therapy might promote castration-resistant PCa.
Funder
Envision Sciences Pty Ltd
NHMRC development grant
Movember Foundation/PCa Foundation of Australia’s Research Program
MTP Connect Biomedical Translation Bridge Program grant
Cancer Council SA Beat Cancer Grant
Cancer Council of SA Beat Cancer Principal Research Fellowship
Publisher
Springer Science and Business Media LLC
Cited by
1 articles.
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